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Ocular and Environmental Factors Associated with Eye Growth in Childhood

Read, Scott Andrew

doi: 10.1097/OPX.0000000000000915
International Myopia Conference Proceedings: Invited Lecture

ABSTRACT Recent advances in measurement technology have improved our ability to quantify a range of ocular components and some environmental exposures that are relevant to myopia. In particular, environmental sensors now allow the dense sampling of personal ambient light exposure data, and advances in ocular imaging, such as developments in optical coherence tomography (OCT), enables high resolution measures of the choroid to be captured in human subjects. The detailed, objective information produced by these noninvasive measurement technologies has the potential to provide important new insights into the complex array of factors underlying eye growth, and myopia development and progression in childhood.

Wearable light sensors and enhanced depth imaging OCT were both employed in a recently completed prospective, observational longitudinal study examining factors associated with eye growth in myopic and non-myopic children. Personal light exposure, choroidal thickness, and axial eye growth were quantified in 101 children over an 18-month period. A significant association was found between objectively measured personal daily ambient light exposure and eye growth (independent of refractive status), consistent with greater light exposure protecting against rapid growth of the eye in childhood. Variations in the thickness of the choroid also appeared to be closely linked to the growth of the eye, with choroidal thinning typically being associated with more rapid eye growth, and choroidal thickening with a slowing of eye growth in childhood. The implications of these findings for our understanding of human eye growth regulation, along with their potential importance for our understanding of myopia control interventions, are discussed.

*PhD, FAAO

School of Optometry and Vision Science, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland, Australia.

The Josh Wallman Memorial Award Keynote Lecture presented at the 15th International Myopia conference, September 23–27, 2015, Wenzhou, China.

Scott A. Read Contact Lens and Visual Optics Laboratory School of Optometry and Vision Science, Queensland University of Technology, Rom D517, O Block, Victoria Park Road Kelvin Grove, Brisbane 4059 Queensland Australia e-mail: sa.read@qut.edu.au

The rising global prevalence of myopia and the associated public health implications of this “myopia boom” provide significant impetus for the development of effective interventions to control the development and progression of myopia.1 Because myopia most commonly occurs due to excessive axial eye growth in childhood, a comprehensive understanding of the ocular and environmental factors associated with childhood eye growth is critical for developing, evaluating, and optimizing myopia control interventions. In the past three decades, sophisticated experiments utilizing a range of animal models2 (many involving the pioneering work of Josh Wallman in the 1990s) and large-scale human epidemiological studies3,4 have substantially expanded our understanding of the various factors underlying the growth of the eye and refractive error development. However, many questions still remain regarding the factors involved in the regulation of eye growth in childhood.

In recent years, technological advances have improved our ability to quantify a range of ocular components and environmental exposures relevant to myopia, and have provided the opportunity to further expand our understanding of human eye growth. In particular, recent advances in ocular imaging technology (such as developments in optical coherence tomography (OCT)) now allow ocular structures such as the choroid to be imaged noninvasively with high precision. The development and proliferation of wearable sensor technology also provides a method to densely sample aspects of the individual’s personal visual environment (e.g. ambient light exposure). Our recent work utilizing these technologies has provided evidence supporting the potentially important role of the choroid5,6 and light exposure7,8 in childhood eye growth. This paper will summarize this recent research examining ocular and environmental factors associated with eye growth in childhood, with a particular emphasis on the findings from the recently completed “Role of Outdoor Activity in Myopia Study” (the ROAM study).

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The Role of Outdoor Activity in Myopia Study

The ROAM study was an 18-month prospective, observational longitudinal study of childhood eye growth conducted between 2012 and 2014 at the Queensland University of Technology, in Brisbane, Australia. The study aimed to provide new insights into the factors underlying childhood eye growth through objective measures of typical daily environmental exposures (i.e. ambient light exposure and physical activity) and high resolution imaging of the choroid in both myopic and non-myopic children.

Detailed descriptions of the participants, and the experimental and analytical methods used in the study have been published previously.5–8 Briefly, 101 children aged between 10 and 15 years (mean age 13.1 ± 1.4 years) were enrolled in the study and the non-cycloplegic spherical equivalent refractive error (SER) measured at the baseline visit was used to classify the children as myopes (n = 41, mean SER: −2.39 ± 1.51 D) or non-myopes (n = 60, mean SER: +0.35 ± 0.31 D). Subject retention over the course of the study was good, with less than 10% attrition of subjects over the 18-month study period. Fig. 1 provides an overview of the experimental protocol employed in the study. Each child had ocular measurements collected every 6 months over an 18-month period (i.e. four visits over 18 months). The primary measurements performed at each visit were optical biometry to determine axial length (AxL, the axial distance between the anterior cornea and the retinal pigment epithelium (RPE)) using the Lenstar LS 900 instrument (Haag Streit AG, Koeniz, Switzerland), and EDI (enhanced depth imaging)9 spectral domain OCT imaging using the Heidelberg Spectralis device (Heidelberg Engineering, Heidelberg, Germany) to derive measures of choroidal thickness (ChT, the axial distance between the RPE and the chorio-scleral interface). In addition to the ocular measurements, in the first 12 months of the study, each child also had objective measures of their personal ambient light exposure and physical activity collected using a wrist-worn sensor device (Actiwatch 2; Philips Respironics, USA). These devices were worn for two 14-day periods, separated by approximately 6 months, and provided instantaneous measures of ambient white light illuminance (wavelength range of 400–900 nm and peak sensitivity of 570 nm with a dynamic sensor range from 5 to 100,000 lux) and physical activity (expressed in activity counts per minute (CPM)) every 30 seconds, 24 hours a day (i.e. 2880 samples of light exposure and physical activity per day across the two 14-day measurement periods for each child). Linear mixed model (LMM) analyses were used to examine the longitudinal changes in AxL and ChT, and the factors (e.g. light exposure, physical activity, and demographic factors) potentially associated with these changes.

FIGURE 1

FIGURE 1

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Choroidal Thickness and Eye Growth

Although the major physiological roles of the choroid (primarily supplying oxygen and nutrients to the outer retina)10 have been well understood for many decades, it is only since the 1990s when Josh Wallman and colleagues11,12 demonstrated that the choroid in developing chickens was capable of changing thickness predictably in response to optical defocus, that evidence for an active role of the choroid in eye growth regulation and refractive error development has emerged. Josh Wallman and Chris Wildsoet’s11,12 seminal work on the chick choroid demonstrated that exposing young chicks to myopic defocus (that results in a slowing of eye growth in the long term and the development of hyperopic refractive errors) resulted in a rapid thickening of the choroid (effectively pushing the retina forwards towards the defocused image plane to compensate for the myopic blur), and exposure to hyperopic defocus (that results in increased axial eye growth and the development of myopia in the long term) resulted in a rapid choroidal thinning (moving the retina back towards the defocused image plane).

Since this first report of a bi-directional choroidal response to defocus in chicks, similar (although smaller magnitude) choroidal responses have been reported in a wide range of animal species including guinea pigs,13 marmosets,14 and macaques.15 In all of these species, choroidal thickening is found to accompany the development of hyperopia (and a slowing of eye growth) and choroidal thinning accompanies the development of myopia (and an increase in eye growth), with the choroidal changes found to occur rapidly and to precede longer term changes in eye growth. In fact, the choroidal changes to defocus in animals have been shown to occur remarkably quickly, with work from the Wallman laboratory in 2005 showing that measurable changes in the chick choroid in response to myopic defocus occur after only 10 minutes of exposure to blur.16 There is also evidence from work in the chick that exposure to defocus can disrupt the normal timing (phase) of the natural diurnal variations that are known to occur in the thickness of the choroid throughout the day.17 The longer term rate of axial eye growth has also been shown to be significantly associated with the difference in phase observed between the choroidal and axial length diurnal rhythms, which suggests that the synchronization of various diurnal rhythms within the eye is important in the normal regulation of eye growth.17

The evidence of a choroidal response to defocus in a wide variety of animal species and the development of highly precise optical methods for the noninvasive assessment of human ocular biometry18 prompted our research laboratory to examine whether a similar short-term response to defocus also occurred in human eyes. In 2010, we published the first evidence in humans that a 60-minute period of myopic defocus results in a small magnitude increase in choroidal thickness and an associated decrease in axial length (because an increase in choroidal thickness would result in a forward movement of the RPE, thus leading to a reduction in the measured axial length), and that 60 minutes of hyperopic defocus results in a thinning of the choroid and an increase in axial length19 (Fig. 2A).

FIGURE 2

FIGURE 2

We expanded upon this initial work using optical biometry and 60 minutes of defocus by studying the effects of a 12-hour period of hyperopic and myopic defocus using spectral domain OCT (Fig. 2B), which also demonstrated a thinning of the choroid in response to hyperopic defocus, and a thickening in response to myopic defocus, primarily evident in the first 3 hours of exposure to blur.20,21 These changes in choroidal thickness observed in response to defocus throughout the day seem to be modulated by an apparent phase shift occurring in the daily changes in choroidal thickness in the myopic defocus condition and by an increase in the daily amplitude of choroidal thickness change in the hyperopic defocus condition (compared to the normal daily changes observed with no defocus), which is also broadly consistent with previous animal studies.17 Similar short-term bi-directional changes in the human choroid in response to defocus have also recently been reported by Chiang et al.22 using OCT imaging and 60 minutes of defocus exposure. It should be noted though that the magnitude of the choroidal response to defocus in humans is very small (around 10–15 μm, which is equivalent to a refractive change of approximately 0.05 D) and therefore unlikely to affect vision or to substantially compensate for the imposed defocus. The bi-directional nature of the response, however, suggests that these changes may reflect biological signals associated with longer term eye growth. The short-term, transient nature of the changes observed to date though means that the link between short-term choroidal changes and longer term eye growth in humans remains to be established.

A number of recent cross-sectional studies using OCT imaging in humans have also shown that choroidal thickness is associated with axial length23–25 (with a thicker choroid being associated with shorter eyes and hyperopia, and a thinner choroid being associated with longer eyes and myopic refractive errors) and that high myopia is associated with marked choroidal thinning.26 Analysis of the OCT imaging data from the baseline visit in the ROAM study also showed that myopic children have significantly thinner choroids than non-myopic children (Fig. 3), and that the differences in thickness between myopes and non-myopes (on average 56 μm thinner in the myopic children) are greater than would be predicted by a passive choroidal stretch associated with the myopic axial elongation.5 These results are consistent with the choroid having a role in the regulation of human eye growth; however, the cross-sectional nature of these reports means that they do not establish a definitive link between choroidal thickness changes and eye growth.

FIGURE 3

FIGURE 3

Longitudinal analyses of the choroidal thickness measures over the 18 months of the ROAM study therefore provide the first assessment of the relationship between the natural changes in choroidal thickness and eye growth occurring in childhood.6 Over the 18-month study period, a significant increase (mean change of 8 μm per year for all children considered together) in choroidal thickness was observed (Fig. 4A), indicating that a thickening of the choroid is a normal feature of the growth of the eye in childhood. Interestingly, studies of nonhuman primates14,15 have also documented developmental increases in choroidal thickness of normally growing adolescent eyes. Although the mechanism underlying these increases in choroidal thickness with age in childhood is not known, it is likely that growth of the choroid’s vascular and connective tissue (and potentially age-related blood flow changes) in childhood are involved.

FIGURE 4

FIGURE 4

In Fig. 4A, the myopic children on average show less choroidal thickening compared to the non-myopic children; however, this trend did not reach statistical significance. But interestingly, considering all children, the changes in choroidal thickness were found to be closely linked to the axial growth of the eye, with a significant inverse association found between the changes in choroidal thickness and the rate of axial eye growth (Fig. 4C). Children exhibiting slower axial eye growth tended to show greater thickening of the choroid over time, and children showing faster axial eye growth displayed less thickening and in many cases a thinning of the choroid. When children were categorized according to their rate of axial eye growth (regardless of refractive status, and based upon a tertile split of the axial eye growth data), the children exhibiting the fastest eye growth in this population were also found to show significantly less choroidal thickening (3.0 μm/year) than those children exhibiting medium (8.9 μm/year) and slow (9.1 μm/year) axial eye growth (Fig. 4B). Because the axial length measurement is defined as the distance from the anterior cornea to the RPE, small changes in the position of the RPE as a direct result of increases and decreases in choroidal thickness may have contributed to the observed association between axial length and choroidal thickness. However, further analyses carried out to calculate the “total eye length” of each subject (the sum of the subfoveal choroidal thickness and axial length, which is effectively the axial distance from the anterior cornea to the front surface of the posterior sclera) over the course of the study also showed a similar significant inverse association between the rate of choroidal thickness change, and the rate of change in total eye length (p < 0.01), supporting a role of the choroid in the regulation of overall eye growth. These choroidal thickness changes observed in human children are also broadly consistent with the previous findings in animal studies, where a slowing in eye growth (during the development of hyperopia or recovery from experimental myopia) is also accompanied by choroidal thickening and an increase in eye growth (during experimental myopia development) is accompanied by choroidal thinning.11–15

The findings from the ROAM study suggest that measures of choroidal thickness are an important biomarker and potentially a novel predictor of the growth of the eye (and hence progression of myopia) in childhood. These findings support an important role for the choroid in the signal cascade involved in the regulation of eye growth in childhood, and provide a catalyst for future research looking at the potential causative link between changes in the choroid and eye growth in childhood. Additional research is required to determine whether the relationship between axial eye growth and choroidal thickness change is due to an active (e.g. the choroid secreting growth factors that act directly on scleral growth) or passive (e.g. the choroid acting as a barrier to the passive diffusion of growth factors) choroidal mechanism. The association found between choroidal thickening and slower eye growth also encourages future investigations of interventions (e.g. optical interventions inducing myopic defocus or pharmacological interventions such as dopamine agonists,10 anticholinergic agents,27 or agents potentiating the effects of nitric oxide28) that are known to result in a thickening of the choroid, to also potentially influence myopia development and progression.

Given that it is only in recent years that reliable measures of choroidal thickness in humans have become possible, there is substantial scope for additional future research to further our understanding of the human choroid and its role in myopia development and progression. To date, published findings regarding the short-term response of the choroid to defocus in humans19–22 have been restricted to populations of young adults. It will therefore be of interest for future studies to examine these choroidal responses in pediatric populations, to explore any differences in the response associated with age, and the potential impact of more rapid eye growth on the responsiveness of the choroid to defocus stimuli. Evidence from animal studies suggests that the mechanisms underlying bi-directional choroidal thickness changes in response to defocus potentially involve a range of factors10–12 such as changes in proteoglycan synthesis or alterations in vascular permeability (that would result in fluid redistribution within the choroid) and/or changes in the tone of nonvascular smooth muscle in the choroid. Further work is required to understand the mechanisms underlying human choroidal thickness changes and to appreciate whether the short-term changes in response to defocus, and the longer term changes occurring during childhood eye growth, share the same mechanisms. The continued evolution of imaging technologies for assessing the human choroid should contribute to new insights into these mechanisms, as imaging much larger regions of the choroid,29 and more detailed characterization of tissue and vascular properties30 (e.g. blood flow and blood vessel architecture) becomes increasingly more possible.

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Light Exposure and Eye Growth

Although the notion that ambient light exposure may impact upon eye growth and myopia dates back at least 100 years,31 the recent findings from epidemiological studies that children with myopia spend less time outdoors than non-myopic children32–35 have sparked a renewed interest in the potential role of light exposure in the regulation of childhood eye growth. The relatively consistent finding (across a range of epidemiological studies of children in a variety of geographic locations) of an association between greater time outdoors and less prevalence32–35 and incidence36–38 of myopia in childhood supports a potential role for light exposure in myopia development because light levels outdoors are substantially brighter than those experienced indoors. However, as well as allowing greater ambient light exposure, being outdoors is also typically associated with less near focusing and more physical activity, and although it has been hypothesized that increased light exposure outdoors is the important factor protecting against myopia (potentially through a mechanism involving light induced release of dopamine which is known to slow eye growth in animals),33 the exact mechanism underlying the protective effects of increased outdoor time on childhood myopia is still not fully understood. One of the reasons for the uncertainty regarding the mechanisms underlying the “outdoor effect” is the fact that the majority of epidemiological studies examining outdoor activity and myopia have relied almost exclusively upon questionnaires to quantify children’s activities. These questionnaires typically involve either a single question or a series of questions about various activities, but regardless of the specific questionnaire used, they all rely on the accuracy of participants’ (or their parents’) memory and perceptions of their previous activities, and additionally do not provide objective, quantitative information regarding the participants actual habitual environment.

A major aim of the ROAM study was therefore to employ objective measures of personal ambient light exposure to examine for the first time the relationship between longitudinal changes in eye growth and light exposure in childhood.8 Comparisons of the ambient light exposure of the myopic and non-myopic children in the ROAM study (derived from the two 14-day periods of wrist-watch light and physical activity measures for each child) revealed that the non-myopic children experienced significantly greater average daily light exposure than the myopic children (Fig. 5). Although all children exhibited similar variations in light exposure throughout the day (with the majority of light exposure occurring between 6 am and 6 pm, and peaks in light exposure observed to coincide with times before and after school, and during the typical breaks in the school day), the non-myopic children were observed to exhibit significantly greater daily light exposure, with the greatest differences associated with refractive error observed in the hour before school starts, lunch hour at school, and in the hour after the end of the school day (Fig. 5). The non-myopic children were also observed to exhibit greater daily time (on average 104 minutes per day) exposed to bright light (light >1000 lux, which is an estimate of outdoor light exposure, because light levels indoors rarely reach 1000 lux) compared to the myopic children (mean of 80 minutes per day). Interestingly, although the physical activity data exhibited similar trends in terms of the daily pattern of change observed, differences between myopic and non-myopic children’s daily physical activity did not reach statistical significance (Fig. 5).

FIGURE 5

FIGURE 5

Consistent with previous studies of childhood eye growth,39–42 examination of the longitudinal changes in eye growth in the ROAM study revealed significantly faster eye growth in the myopic children compared to the non-myopic children (Fig. 6A) and significantly faster eye growth associated with younger age. A modest but statistically significant inverse association between eye growth and average daily light exposure was also observed, with greater daily light exposure being associated with significantly slower axial eye growth. This analysis also revealed that daily physical activity was not a significant predictor of axial eye growth in childhood. These results provide the first evidence of a significant relationship between objectively measured ambient daily light exposure and axial eye growth in childhood, and support the theory that ambient bright light exposure is the important factor involved in the documented association between outdoor activity and myopia. Because bright light is also known to induce the release of retinal dopamine,43 these findings of an association between childhood eye growth and light exposure also support the previous hypothesis that the mechanisms underlying the anti-myopiagenic effects of outdoor activity involve dopamine.33

FIGURE 6

FIGURE 6

Additional analyses were also performed after classifying the children in the study according to their average daily light exposure (based upon a tertile split of the average daily light exposure data, regardless of refractive grouping), as either habitually experiencing low daily light exposure, moderate daily light exposure, or high daily light exposure. Examination of the axial eye growth in these three groups of children revealed statistically significantly faster axial eye growth (0.13 mm/year) in the children habitually exposed to low light levels compared to those children habitually exposed to high (0.065 mm/year) and moderate (0.060 mm/year) light levels (who were not significantly different to each other) (Fig. 6B). Because the low light exposure group on average spent only 56 minutes per day exposed to bright light (>1000 lux), these findings suggest that less than 60 minutes of bright light exposure per day predisposes children to faster axial eye growth/greater myopia progression. When we examine the average magnitude of difference in eye growth between these light exposure groups, the children habitually experiencing low daily light exposure exhibited approximately 0.1 mm greater eye growth over the course of the study, which equates to ~0.3 D greater myopic refractive progression. These analyses include adjustments for potential confounders, including age and refractive grouping, which suggests that the association between light exposure group and eye growth was independent of refractive status.

These findings support the potential for strategies aimed at increasing daily ambient light exposure as potential myopia control interventions, and also provide some insights into the potential strength of the effects and “dosages” required in such interventions. The children in the ROAM study habitually experiencing moderate and high daily light exposure on average experienced 60 more minutes per day exposure to bright light compared to the children habitually experiencing low light exposure, and also exhibited significantly slower eye growth. This suggests therefore that increasing exposure to bright light (>1000 lux) by around 60 minutes per day is likely to have an impact on slowing axial eye growth in childhood. Two recent studies44,45 have examined the influence of increasing outdoor time (aiming to increase children’s daily time outdoors by 40 minutes45 and 80 minutes44) upon childhood refractive development and have noted positive effects of these interventions upon reducing myopia development; however, neither of these studies objectively assessed the light exposure of the participants. The findings from these studies with respect to myopia progression, however, have been less clear cut since Wu et al.44 found a significant effect of their outdoor intervention upon refractive progression only in those children who were non-myopic at the start of the trial (and not in myopic children), and although He et al.45 did find a significant reduction in myopia progression associated with their outdoor intervention, they did not find any statistically significant effects of the intervention upon axial eye growth measures. This highlights the need for further research to better understand the influence of increasing light exposure upon myopia progression and eye growth. The use of wearable light sensors in future interventional studies should help to expand the understanding of these effects by allowing detailed quantification of exposure in treatment and control groups (and providing an objective means of assessing compliance with the intervention). This could also help to clarify if changes in specific light exposure parameters (e.g. intensity and/or duration of daily exposure) have an influence upon refractive progression and eye growth. Such an improved understanding may in turn allow the optimization of future interventions to further reduce the development and progression of myopia.

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Light Exposure and Choroidal Thickness

The findings from the ROAM study indicate that both ambient light exposure and choroidal thickness6 are associated with the axial growth of the eye in childhood. There is also evidence from animal studies46 that exposure to bright light can lead to a small magnitude of choroidal thickening. Human studies also indicate that altering the pattern of light exposure can influence choroidal blood flow.47,48 These findings leave open the possibility that the influence of light exposure upon eye growth may involve (at least in part) a choroidal mechanism. To explore this issue further, here we have also examined the potential association between light exposure and choroidal thickness in the children participating in the ROAM study. The choroidal thickness changes over time were examined after categorizing the children based upon their average daily light exposure as habitually experiencing low, moderate, or high light exposure (Fig. 7). This analysis revealed that children habitually experiencing moderate and high daily ambient light exposure exhibited significantly greater choroidal thickening over time compared to children habitually experiencing low light exposure (p = 0.001). However, it should be noted that the close relationship previously observed between light exposure and eye growth, and between eye growth and choroidal thickness make it difficult to assess, based upon these data alone, whether the changes in the choroid in the different light exposure groups are an independent effect of light on the choroid or an indirect effect related to the association between light and eye growth. This result, however, does suggest that the mechanisms linking light exposure and eye growth could potentially involve the choroid, and encourages future research to examine the effects of light exposure upon choroidal thickness in childhood.

FIGURE 7

FIGURE 7

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CONCLUSIONS

The work presented in this paper exploits developments in ocular imaging and sensor technology to provide new insights into the ocular and environmental factors involved in childhood eye growth, demonstrating that choroidal thickness changes seem to be providing an ocular biomarker of eye growth in childhood and that ambient light exposure is a modifiable environmental factor associated with eye growth in childhood. These techniques seem to provide robust tools for quantifying ocular changes and environmental effects in myopia research, and the continued use and development of these methodologies in the future will continue to expand our understanding of the factors underlying myopia and should assist in the development and optimization of myopia control interventions.

Scott A. Read

Contact Lens and Visual Optics Laboratory

School of Optometry and Vision Science

Queensland University of Technology

Rom D517, O Block, Victoria Park Road

Kelvin Grove, Brisbane 4059

Queensland

Australia

e-mail: sa.read@qut.edu.au

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ACKNOWLEDGMENTS

The ROAM study was supported by an Australian Research Council Discovery Early Career Researcher Award (DE120101434). The author thanks co-investigators David Alonso-Caneiro, Ranjay Chakraborty, Michael Collins, Beata Sander, and Stephen Vincent for their valuable contributions to the work presented in this paper. The support of the Young Investigator in Myopia Research award by Carl Zeiss is also gratefully acknowledged.

This article is based upon the Josh Wallman Memorial Award Keynote Lecture presented at the 15th International Myopia conference, September 23–27, 2015, Wenzhou, China.

Received January 5, 2016; accepted April 7, 2016.

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REFERENCES

1. Holden B, Sankaridurg P, Smith E, Aller T, Jong M, He M. Myopia, an underrated global challenge to vision: where the current data takes us on myopia control. Eye 2014;28:142–6.
2. Wallman J, Winawer J. Homeostasis of eye growth and the question of myopia. Neuron 2004;43:447–68.
3. Morgan I, Rose K. How genetic is school myopia? Prog Retin Eye Res 2005;24:1–38.
4. French AN, Ashby RS, Morgan IG, Rose KA. Time outdoors and the prevention of myopia. Exp Eye Res 2013;114:58–68.
5. Read SA, Collins MJ, Vincent SJ, Alonso-Caneiro D. Choroidal thickness in myopic and nonmyopic children assessed with enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci 2013;54:7578–86.
6. Read SA, Alonso-Caneiro S, Vincent SJ, Collins MJ. Longitudinal changes in choroidal thickness and eye growth in childhood. Invest Ophthalmol Vis Sci 2015;56:3103–12.
7. Read SA, Collins MJ, Vincent SJ. Light exposure and physical activity in myopic and emmetropic children. Optom Vis Sci 2014;91:330–41.
8. Read SA, Collins MJ, Vincent SJ. Light exposure and eye growth in childhood. Invest Ophthalmol Vis Sci 2015;56:6779–87.
9. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500.
10. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29:144–68.
11. Wallman J, Wildsoet C, Xu A, Gottlieb MD, Nickla DL, Marran L, Krebs W, Christensen AM. Moving the retina: choroidal modulation of refractive state. Vision Res 1995;35:37–50.
12. Wildsoet C, Wallman J. Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vision Res 1995;35:1175–94.
13. Howlett MH, McFadden SA. Spectacle lens compensation in the pigmented guinea pig. Vision Res 2009;49:219–27.
14. Troilo D, Nickla DL, Wildsoet CF. Choroidal thickness changes during altered eye growth and refractive state in a primate. Invest Ophthalmol Vis Sci 2000;41:1249–58.
15. Hung LF, Wallman J, Smith EL 3rd. Vision-dependent changes in the choroidal thickness of Macaque monkeys. Invest Ophthalmol Vis Sci 2000;41:1259–69.
16. Zhu X, Park TW, Winawer J, Wallman J. In a matter of minutes, the eye can know which way to grow. Invest Ophthalmol Vis Sci 2005;46:2238–41.
17. Nickla DL. The phase relationships between the diurnal rhythms in axial length and choroidal thickness and the association with ocular growth rate in chicks. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2006;192:399–407.
18. Buckhurst PJ, Wolffsohn JS, Shah H, Naroo SA, Davies LN, Berrow EJ. A new optical low coherence reflectometry device for ocular biometry in cataract patients. Br J Ophthalmol 2009;93:949–53.
19. Read SA, Collins MJ, Sander BP. Human optical axial length and defocus. Invest Ophthalmol Vis Sci 2010;51:6262–9.
20. Chakraborty R, Read SA, Collins MJ. Monocular myopic defocus and daily changes in axial length and choroidal thickness of human eyes. Exp Eye Res 2012;103:47–54.
21. Chakraborty R, Read SA, Collins MJ. Hyperopic defocus and diurnal changes in human choroid and axial length. Optom Vis Sci 2013;90:1187–98.
22. Chiang ST, Phillips JR, Backhouse S. Effect of retinal image defocus on the thickness of the human choroid. Ophthalmic Physiol Opt 2015;35:405–13.
23. Esmaeelpour M, Povazay B, Hermann B, Hofer B, Kajic V, Kapoor K, Sheen NJ, North RV, Drexler W. Three-dimensional 1060-nm OCT: choroidal thickness maps in normal subjects and improved posterior segment visualization in cataract patients. Invest Ophthalmol Vis Sci 2010;51:5260–6.
24. Li XQ, Larsen M, Munch IC. Subfoveal choroidal thickness in relation to sex and axial length in 93 Danish university students. Invest Ophthalmol Vis Sci 2011;52:8438–41.
25. Vincent SJ, Collins MJ, Read SA, Carney LG. Retinal and choroidal thickness in myopic anisometropia. Invest Ophthalmol Vis Sci 2013;54:2445–56.
26. Fujiwara T, Imamura Y, Margolis R, Slakter JS, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol 2009;148:445–50.
27. Sander BP, Collins MJ, Read SA. The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults. Exp Eye Res 2014;128:181–9.
28. Vance SK, Imamura Y, Freund KB. The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. Retina 2011;31:332–5.
29. Mohler KJ, Draxinger W, Klein T, Kolb JP, Wieser W, Haritoglou C, Kampik A, Fujimoto JG, Neubauer AS, Huber R, Wolf A. Combined 60° wide-field choroidal thickness maps and high-definition en face vasculature visualization using swept-source megahertz OCT at 1050 nm. Invest Ophthalmol Vis Sci 2015;56:6284–93.
30. Ferrara D, Waheed NK, Duker JS. Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies. Prog Retin Eye Res 2016;52:130–55.
31. Cohn H. Handbook of the Hygiene of the Eye. Vienna and Leipzig: Urban & Schwarzenegger; 1892.
32. Mutti DO, Mitchell GL, Moeschberger ML, Jones LA, Zadnik K. Parental myopia, near work, school achievement, and children’s refractive error. Invest Ophthalmol Vis Sci 2002;43:3633–40.
33. Rose KA, Morgan IG, Ip J, Kifley A, Huynh S, Smith W, Mitchell P. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008;115:1279–85.
34. Dirani M, Tong L, Gazzard G, Zhang X, Chia A, Young TL, Rose KA, Mitchell P, Saw SM. Outdoor activity and myopia in Singapore teenage children. Br J Ophthalmol 2009;93:997–1000.
35. Guo Y, Liu LJ, Xu L, Lv YY, Tang P, Feng Y, Meng M, Jonas JB. Outdoor activity and myopia among primary students in rural and urban regions of Beijing. Ophthalmology 2013;120:277–83.
36. Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger ML, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci 2007;48:3524–32.
37. Guggenheim JA, Northstone K, McMahon G, Ness AR, Deere K, Mattocks C, Pourcain BS, Williams C. Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study. Invest Ophthalmol Vis Sci 2012;53:2856–65.
38. French AN, Morgan IG, Mitchell P, Rose KA. Risk factors for incident myopia in Australian schoolchildren. The Sydney Adolescent Vascular and Eye Study. Ophthalmology 2013;120:2100–8.
39. Saw SM, Nieto FJ, Katz J, Schein OD, Levy B, Chew SJ. Factors related to the progression of myopia in Singaporean school children. Optom Vis Sci 2000;77:549–54.
40. Gwiazda J, Hyman L, Hussein M, Everett D, Norton TT, Kurtz D, Leske MC, Manny R, Marsh-Tootle W, Scheiman M. A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 2003;44:1492–500.
41. Zadnik K, Mutti DO, Mitchell GL, Jones LA, Burr D, Moeschberger ML. Normal eye growth in emmetropic schoolchildren. Optom Vis Sci 2004;81:819–28.
42. Jones LA, Mitchell GL, Mutti DO, Hayes JR, Moeschberger ML, Zadnik K. Comparison of ocular component growth curves among refractive error groups in children. Invest Ophthalmol Vis Sci 2005;46:2317–27.
43. Brainard GC, Morgan WW. Light-induced stimulation of retinal dopamine: a dose response relationship. Brain Res 1987;424:199–203.
44. Wu PC, Tsai CL, Wu HL, Yang YH, Kuo HK. Outdoor activity during class recess reduces myopia onset and progression in school children. Ophthalmology 2013;120:1080–5.
45. He M, Xiang F, Zeng Y, Mai J, Chen Q, Zhang J, Smith W, Rose K, Morgan IG. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA 2015;314:1142–8.
46. Lan W, Feldkaemper M, Schaeffel F. Bright light induces choroidal thickening in chickens. Optom Vis Sci 2013;90:1199–206.
47. Longo A, Geiser M, Riva CE. Subfoveal choroidal blood flow in response to light-dark exposure. Invest Ophthalmol Vis Sci 2000;41:2678–83.
48. Lovasik JV, Kergoat H, Wajszilber MA. Blue flicker modifies the subfoveal choroidal blood flow in the human eye. Am J Physiol Heart Circ Physiol 2005;289:H683–91.
Keywords:

eye growth; myopia; choroid; light exposure; optical coherence tomography

© 2016 American Academy of Optometry